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High cortisol and aldosterone levels increase cardiovascular risk, but the respective roles of each hormone within the arterial wall remain controversial. We tested the hypothesis that cortisol production within the arterial wall may contribute to atherosclerotic remodeling and act through illicit activation of the mineralocorticoid receptor (MR). Gene expression studies of the corticoid system components and marker genes of the atherosclerotic process in human carotid atheroma plaque and nearby macroscopically intact tissue (MIT) were considered together with clinical data and compared with pharmacological stimulations of human vascular smooth muscle cells (VSMCs) in contractile or lipid-storing phenotypes. The components of corticoid production and action were present and active within the human carotid wall and VSMCs. Atheroma plaque and lipid-storing VSMCs expressed 11β-hydroxysteroid deshydrogenase-1 (11β-HSD1) at two- to tenfold higher levels than MIT or contractile VSMCs. The 11β-HSD1 expression was stimulated by cortisol and cortisone, especially in lipid-storing VSMCs. MR mRNA level was lower in atheroma and lipid-storing VSMCs and downregulated via MR by fludrocortisone and cortisol. Cortisol upregulated collagen1 and MCP-1 mRNAs via the glucocorticoid receptor (GRα), in both VSMC phenotypes, whereas fludrocortisone stimulated the collagen1 expression only in lipid-storing VSMCs. The GRα mRNA level in MIT was higher in patients with previous stroke and correlated positively with the collagen1 mRNA but negatively with diastolic blood pressure. Local cortisol production by 11β-HSD1, and its action via high parietal GRα could be relevant from the first step of atherosclerotic remodeling and auto-amplify with transdifferentiation of VSMCs during atheroma progression., (© 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.)

The involvement of the renin-angiotensin-aldosterone system (RAAS) and cortisol in increased cardiovascular risk is well known. If numerous relationships between RAAS and corticosteroids have been described, their interactions within the arterial wall, especially during the transdifferentiation of vascular smooth muscle cells (VSMCs) and the atheroma formation, are not established. Here, we clarified the relationships between mRNA levels of corticosteroid and angiotensin system components using cortisol, fludrocortisone, and angiotensin II treatments of cultured VSMCs maintained in a contractile phenotype or induced to a lipid storing phenotype. We then determined the quantitative relationships between the mRNA content of these components measured with reverse transcription polymerase chain reaction (RT-PCR), in the atheroma plaque and nearby macroscopically intact tissue (MIT) from 27 human carotid endarterectomy samples. In both VSMC phenotypes, cortisol markedly increased both angiotensinogen (AGT) and AT1-receptor (AT1R) mRNA levels. These effects of cortisol were mediated via glucocorticoid receptor-α (GRα) without any illicit activation of the mineralocorticoid receptor (MR). Angiotensin II increased GRα, 11βHSD1, CYP11B1, as well as CYP11B2 mRNAs and decreased AT1R in contractile VSMC; only GRα and CYP11B2 were increased in lipid storing VSMCs, while MR and AGT mRNAs decreased. In endarterectomy specimens, positive correlations between mRNA levels of AGT and aldosterone synthase or 11βHSD1 in MIT and of AT1R and MR in atheroma were detected. The arterial tissue angiotensin system is a target for local glucocorticoids and arterial glucocorticoids for angiotensin II. Both systems appear activated in lipid storing VSMCs and strongly correlated in vivo, and their mutual amplification may contribute to the development of atheroma. Key message: [ABSTRACT FROM AUTHOR]